The tick borne encephalitis (TBE) complex of viruses (genus: Flaviviridae), which includes Tick borne encephalitis virus (TBEV), Omsk hemorrhagic fever virus and Kyasanur forest disease virus, are listed among the NIAID category B and C lists of priority for research into pathogenesis, treatment and vaccine development. As their name suggests, the TBE viruses are transmitted by ticks, and following infection of humans, cause encephalitis, meningitis or hemorrhagic fevers with mortality rates as high as 40%. In a new initiative in the laboratory, three research directions are being undertaken to understand the pathogenesis of TBE viruses and to develop strategies for theraputics and vaccine candidates. The first project is the determination of the mechanism of viral inhibition of interferon responses. Interferon treatment of humans is a leading therapeutic candidate for flavivirus infection. However, such treatment often fails. We have shown that although TBE viruses are highly susceptible to the antiviral action of inferferons prior to infection, TBEV can inhibit the interferon signaling pathways (called the JAK-STAT pathway) following infection. This inhibition occurs in primary mouse and human dendritic cells infected with TBEV. We are currently identifying the viral protein responsible and the precise mechanism of interference. The second study compares virus replication in mammalian cell lines and tick cell lines. Currently, TBEV is being repeatedly passaged in these cells and the cell-adapted viruses inoculated into mice to identify viruses differing in virulence. These viruses will then be sequenced to identify virulence factors and potentially identify virus-encoded determinants of persistence. The third study aims to develop DNA-based virus-subunit vaccines. Current TBEV vaccines are live-attenuated or killed-virus vaccines, making them expensive to produce and have a number of safety issues associated with them. To abate these concerns, we aim to identify viral cDNA sequences for use in a DNA expression vector. Following inoculation of these constructs into mice, the protein expression will illicit an immune response sufficient to protect against infection with any of the viruses belonging to the TBE complex.